Nitrogen-Only Heterocycles

Mechanistically, this transformation was proposed to start by the formation of enaminone 5 from 1 and L-Pro, which is faster than a similar reaction starting from 3, followed by a Knoevenagel reaction with 3 and subsequent hydrolysis to give 6. A Michael addition of 2 to 6 followed by a final cyclocondensation with loss of a molecule of water would explain the isolation of the final dihydropyridine 4 [9], 

Some other multicomponent processes have been developed that give access to dihydropyridines and are complementary to the Hantzsch reaction in terms of scope. Among them, we will mention the reaction between anilines, p-dicarbonyl compounds, and cinnamaldehyde in the presence of cerium(IV) ammonium nitrate to give 

Other groups have attempted to carry out this reaction in the presence of several amino acids, including l-Pto, under solvent-free conditions [15], and thiourea derivatives as organocatalysts [16], although so far only modest enantiomeric excesses have been achieved. 

In 2006, Orru and coworkers reported a very highly diastereoselective four-component reaction for the synthesis of functionalized dihydropyridin-2-ones from 

An elegant approach to the diastereoselective synthesis of densely functionalized 1,2,5,6-tetrahydropyridines 31 based on the a,Y-difunctionalization of 1,3-dicarbonyl compounds was pioneered in 2007 by Clarke [23], and then followed up by other groups [24-26], It generates five new eovalent bonds and proceeds via a domino pseudo five-component reaction from anilines, aromatic aldehydes (2 equiv. of each). 

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Five-Membered Nitrogen-Only Heterocycles and their Fnsed Derivatives... 

In conclusion, in terms of electrophilic reactivity a methyl group in the 2-position is equally reactive in the two categories of heterocycles (selenazole and thiazole). Of the two positions ortho to nitrogen, only the 2-position is activated. The 5-position is sensitive to electrophilic reagents and resembles more closely the para position of a benzene ring. 

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

Chalcone dibromides are advantageous intermediates for the preparation of various nitrogen-containing heterocycles (refs. 1-4). In the case of exocyclic a,P-unsaturated ketones, however, only few examples are known concerning the utilization of their dibromides for such purposes (ref. 5). Our aim was, therefore, the synthesis of the dibromides of various exocyclic a,P-unsaturated ketones (ref. 6) and to study their chemical transformations. In our present paper the reaction of such dibromides with azide nucleophile is reported. 

The initial success of the reactive dyes based on the triazine ring system was immediately followed by intense research activity into the possibilities offered by other related nitrogen-containing heterocyclic systems. Numerous systems have been patented as fibre-reactive groups although only a few of these have enjoyed significant commercial success. Some examples are illustrated in Figure 8.2. They include the trichloro-pyrimidines 176, the dichloropyridazines 177, the dichloroquinoxalines 178 and the chlorobenzothiazolyl dyes 179. 

HMBC experiments are not limited to proton-carbon interaction. With suitable hardware, it is possible to acquire 1H-I5N spectra which can be extremely useful for confirming the identity of nitrogen-containing heterocyclic compounds. The sensitivity of this technique is very low, probably only about... 

In other words, a synthetic route to polypeptides which requires only HCN and water is presented preformed a-amino acids are not necessary. According to Matthews, the pyrolysis of cyanide polymers can give nitrogen-containing heterocycles with purine and pyrimidine structures in other words, the HCN world ... 

Reports of [ 2 + 2] cycloaddition of nitrogen containing heterocycles to alkenes are so numerous that attention can be drawn here to only a few. Recent examples include the acetone-sensitized photoaddition of 4-oxazolin-2-one (248) to ethylene to give the cis-adduct 249,203 the photocycloadditions of N-substituted imidazoles to acrylonitrile204 and of N-methyl-4-hydroxy-quinol-2-one to cyclohexene,205 and the photoaddition of pentafluoro-pyridine to ethylene to give the 1 1- and 1 2-adducts 250 and 251,... 

In conclusion, the Pd chemistry of pyrimidines has its own characteristics when compared to carbocyclic arenes and other nitrogen-containing heterocycles such as pyridine and imidazole. One salient feature of halopyrimidines is that the C(4) and C(6) positions are more activated than C(2). As a result, 2-, 4- and 6-chloropyrimidines are viable substrates for Pd-catalyzed reactions and 4- and 6-chloropyrimidines react more readily than 2-chloropyrimidines. For the Sonogashira reaction, though, there is little difference in the reactivity among 2-, 4- and 5-positions of substituted halopyrimidines. Not only is the Sonogashira reaction a reliable method... 

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

Of the possible four-membered sulfur-containing heterocyclic rings that contain another heteroatom, which is not sulfur, oxygen, or nitrogen, only the thiaphosphetanes, silathietanes, and selenathietanes are discussed in the literature up to 1980. 

The reaction of 113 with several Af-lithioamines was investigated and the results are summarized in Table 5. Af-Methylaniline, p-chloro-Af-methylaniline and Af-benzyl-p-anisidine gave 60-67% yield of the desired Af-cyclopropyl arylamines. Diphenylamine gave the desired product however, the yield was not satisfactory. Interestingly, dibenzy-lamine did not afford the desired product at all. This result indicated that the magnesium cyclopropylidene (113) only reacts with Af-lithio arylamines. The reaction of 113 with Af-lithio nitrogen-containing heterocyclic compounds was also studied. From the results shown in Table 5, the yields of the reaction are variable as a function of the heterocyclic compounds used. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Oxygen only Nitrogen only AH other types of heterocycle... 

Figure 10-2. Although they are relatively rare in biology, organometallic compounds with metal-carbon bonds are important. An typical example is coenzyme B12. The cobalt is co-ordinated to a tetraazamacrocyclic ligand, and has one axial nitrogen donor heterocyclic ligand and one axial alkyl group. The figure illustrates only the core of the macrocycle and the axial groups.

In the series of stable five-membered nitrogen-containing heterocycles, tetrazole possesses extreme characteristics that are inferior only to those of pentazole (cf. Section 6.07.4.3). Attention should be paid to the obvious fact that, in contrast to the hypothetical pentazole, tetrazole is a thermodynamically stable compound. This heterocycle surpasses the simple azide and hydrazoic acid by a number of key tests. However, tetrazoles are thermodynamically stable in the condensed phase, relatively weakly sensitive to impact and friction, and not very toxic, unlike HN3 which is notorious for its high sensitivity to impact, friction, thermal and electric impulses, and toxicity <1999THS(3)467>. 

Heterocycles with elements of group V are known too, chiefly with nitrogen. Only a few compounds with phosphorus have been described. Nonaphenyl-phosphocyclopentasilane is formed by the reaction described above256) ... 

Nitrogen-based heterocycles can also be prepared through Ni/NHC-catalyzed cyclo addition reactions. For example, Ni/SIPr catalyzed the cycloaddition of diynes with isocyanates under the mildest conditions to date [26]. In particular, excellent yields of pyridones are obtained from diynes and isocyanates at room temperature using only 3 mol % catalyst. As shown in Eq. 8, a variety of diynes were subjected to these optimized conditions. Both aryl and alkyl isocyanates were readily converted to the respective 2-pyridone. Sterically hindered substrates appeared to have very little effect on the reaction, as excellent yields of product were obtained with bulky isocyanates and bulky diynes. 

As with other nitrogen-containing heterocycles, TV-alkylation is a reaction of some interest. This is particularly true when the products are nucleosides. One interesting example of nucleoside formation arises from reaction of a suitable furo[3,4-J]pyrimidine (41) and l-O-acetyl-2,3,5-tribe nzoyl-/ -D-ribose the product formed seems to be solvent dependent. The N-l substituted nucleoside (42 R = tribenzoylribose) is formed in 81 % yield when the heterocycle and the protected sugar are treated with tin(IV) chloride in acetonitrile. However, use of 1,2-dichloroethane as solvent affords only 17% of this product together with 81% of the N-l,N-3 disubstituted product (Equation (10)) <83CPB3074>. 

As far as ring hydroxylation is concerned, it appears that hydroxy groups are always introduced in position para to tlie heterocyclic nitrogen. Only monohydroxy derivatives are usually found. Nevertheless, 2-chlorothionol has been identified among the metabolic... 

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